Polymorphonuclear neutrophils (PMNs) are an important component of innate immunity. In the intestine PMNs are rapidly recruited towards the regions that have been compromised by invading bacterial pathogens, thus providing the first line of defense. However, their influx into mucosa also characterizes many inflammatory diseases including Crohn's and Ulcerative Colitis where increased numbers of infiltrating PMNs cause damage to the intestinal wall. During inflammation PMNs exit the blood vessels and are driven towards and across epithelium by chemoattracting forces. Diffusion of bacterial derived peptides, such as fMLF, across epithelial layer as well as basolateraly secreted epithelium-derived chemokines, such as IL-8, establish a chemoattractant gradient that guides PMNs towards the sites of inflammation. PMNs encountering proinflammatory stimuli undergo morphological changes as well as changes in the expression of surface adhesive receptors. For example, β2-integrin CD11b/CD18, which is important for the initial PMN adhesion to both endothelium and epithelium, is upregulated upon PMN activation. In contrast, expression of L-selectin, another adhesive receptor that mediates initial PMN rolling in blood vessels, is completely lost upon PMN activation and migration.
Epithelial and endothelial proteins expressed at intercellular junctions and members of the immunoglobulin superfamily (IgSf) members have been implicated directly or indirectly in regulating PMN trafficking and a variety of epithelial/endothelial cell functions. Function of these proteins is, in part, mediated through homo- and heterotypic interactions with related family members and integrins. JAM-A, for example is abundantly expressed at the epithelial apical junctional complexes (AJC) as well as on PMNs. PMNs from JAM-A deficient mice (JAMA −/−) exhibit impaired migration. Another related molecule, JAML, is not present in epithelial or endothelial cells.
JAML has been shown to bind specifically to the cosackie adenovirus receptor (CAR), which is another member of the Ig superfamily. CAR is expressed at tight junctions of epithelial cells and to some degree on subtypes of endothelial cells, and localizes to the tight junctions (TJ). Both JAML and CAR are type I glycoproteins composed of two extracellular immunoglobulin domains, a single transmembrane helix, and a cytoplasmic domain. CAR has been shown to form homodimers in cis via the membrane distal D1 domain. CAR has been implicated in regulating epithelial permeability and cell adhesion to extracellular matrix by controlling the localization of cell integrins. JAML plays a role in regulating monocyte transendothelial migration and neutrophil transepithelial migration by binding to the endothelial CAR and other tight junction-associated adhesive molecules. See Zen et al., Mol. Biol. Cell, 2005, 16(6):2694-2703, Ya-Lan et al., Arteriosclerosis, Thrombosis, and Vascular Biology, 2009, 29: 75-83, and Witherden et al., Science, 2010, 329 (5996): 1205-1210. CAR and JAML are cell signaling receptors of the immune system with implications for asthma, cancer, and chronic non-healing wounds. See Verdino et al., Science, 2010, 1210-1211.
Monoclonal anti-mouse JAML antibody (clone 4E10) may be purchased from eBiosciences. See also Luissint et al., J Cell Biol, 2008, 183:1159-1173; U.S. Pat. No. 8,017,344; and U.S. Published Application No. 2008/0248502.